Role of Receptor for Advanced Glycation End Product (RAGE) Pathway in Brain Tumor

高级糖基化终产物 (RAGE) 通路受体在脑肿瘤中的作用

• 批准号: 8329598
• 负责人: Behnam Badie
• 金额: $ 34.86万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-07 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8329598
• 关键词: Acute; Advanced Glycosylation End Products; Astrocytoma; Binding; Binding Proteins; Brain; Brain Neoplasms; Brain Pathology; Carbon Nanotubes; Cells; Cerebrum; Combined Modality Therapy; Development; Diffuse; Disease; Environment; Gene Expression; Glioma; Goals; Growth; HMGB1 gene; Human; Hypoxia; Immune; Immune response; Immune system; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Implant; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Kinetics; Knowledge; Lead; Ligands; MAP Kinase Gene; MAPK3 gene; Macrophage Activation; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Mediating; Mediator of activation protein; Membrane; Microdialysis; Microglia; Modeling; Molecular; Mus; Myelogenous; Neoplasm Metastasis; Oxidative Stress; Pathway interactions; Patients; Play; Process; Proteins; Receptor Activation; Receptor Inhibition; Regulation; Research; Rodent; Role; S100A8 gene; S100A9 gene; STAT3 gene; Small Interfering RNA; Stroke; Surface; TYK2; Techniques; Testing; Therapeutic; Trauma; Vascular blood supply; angiogenesis; conventional therapy; cytokine; glycation; immune activation; immune function; immunoregulation; improved; inhibitor/antagonist; innate immune function; innovation; innovative technologies; macrophage; monocyte; nanoparticle; neoplastic cell; novel; pathogen; receptor; receptor for advanced glycation endproducts; response; response to injury; tumor; tumor progression

DESCRIPTION (provided by applicant): With a two-year survival of less than 20%, malignant gliomas are among the most fatal cancers in humans. Although immunotherapy is being studied as a possible treatment for malignant brain tumors, the immunosuppressive glioma environment has limited the efficacy of this approach. As active mediators of the innate immune response, microglia (MG) and macrophages (MPs) constitute the first line of cellular defense against brain pathogens. Our group and others have shown that the effector function of MG/MPs appears to be suppressed in gliomas through activation of STAT3, yet the exact mechanism by which gliomas induce STAT3 in MG/MPs is unknown. We recently demonstrated that exposure of MG to glioma factors and to low (nM) levels of S100B, a Ca2+binding protein that is highly expressed in astrocytomas, upregulated receptor for advanced glycation end products (RAGE, a S100B receptor), induced STAT3, and inhibited MG proinflammatory function in vitro. Furthermore, blockage of RAGE inhibited STAT3 activity in cultured MG and in MG/MPs in murine gliomas. These findings suggest that the RAGE pathway may play an important role in TAM inactivation and STAT3 induction, and that this process may be mediated through secretion of S100B by glioma cells. Thus, we hypothesize that MG/MP immune function in gliomas is modulated by S100B through engagement of RAGE and inhibition of this pathway may further enhance MG/MP pro-inflammatory function in gliomas. To further study this novel glioma-MG/MP interaction, we will first measure levels of RAGE ligands in i.c. gliomas. Cerebral microdialysis technique will be used to measure intratumoral concentrations of RAGE- activating factors (S100B, S100A8, S100A9, HMGB1, and AGEs) in human gliomas propagated in rodents. These studies will provide important information on S100B and other known RAGE ligands that are secreted in the tumor microenvironment and potentially involved in MG/MP STAT3 activation. In the second aim, we will evaluate the effect of S100B/RAGE inhibition on tumor MP function. RAGE/RAGE ligand interactions will be selectively inhibited and MG/MP immune activation will be studied in murine glioma models. Finally, in the last aim, we will study the molecular mechanisms by which S100B activates STAT3 through the RAGE pathway in tumor MG/MPs. Results from these studies will have significant impact on current treatment of brain tumors as blockage of S100B-RAGE pathway may lead to MG/MP activation and enhancement of immunotherapeutic approaches against diffuse gliomas.

描述（由申请人提供）：恶性神经胶质瘤的两年生存率低于 20%，是人类最致命的癌症之一。尽管正在研究免疫疗法作为恶性脑肿瘤的可能治疗方法，但免疫抑制神经胶质瘤环境限制了这种方法的功效。作为先天免疫反应的主动介质，小胶质细胞（MG）和巨噬细胞（MP）构成了针对脑部病原体的细胞防御的第一道防线。我们的小组和其他人已经表明，神经胶质瘤中 MG/MP 的效应功能似乎通过 STAT3 的激活而受到抑制，但神经胶质瘤在 MG/MP 中诱导 STAT3 的确切机制尚不清楚。我们最近证明，将 MG 暴露于神经胶质瘤因子和低 (nM) 水平的 S100B（一种在星形细胞瘤中高表达的 Ca2+ 结合蛋白，上调晚期糖基化终产物受体（RAGE，S100B 受体））会诱导 STAT3，并在体外抑制 MG 促炎功能。此外，阻断 RAGE 可抑制培养的 MG 和小鼠神经胶质瘤中 MG/MP 中的 STAT3 活性。这些发现表明，RAGE 通路可能在 TAM 失活和 STAT3 诱导中发挥重要作用，并且该过程可能是通过神经胶质瘤细胞分泌 S100B 介导的。因此，我们假设神经胶质瘤中的 MG/MP 免疫功能是由 S100B 通过 RAGE 参与调节的，抑制该通路可能会进一步增强神经胶质瘤中 MG/MP 的促炎功能。为了进一步研究这种新型神经胶质瘤-MG/MP 相互作用，我们将首先测量 i.c. 中 RAGE 配体的水平。神经胶质瘤。脑微透析技术将用于测量在啮齿类动物中传播的人类神经胶质瘤中 RAGE 激活因子（S100B、S100A8、S100A9、HMGB1 和 AGE）的瘤内浓度。这些研究将提供有关 S100B 和其他已知的 RAGE 配体的重要信息，这些配体在肿瘤微环境中分泌，并可能参与 MG/MP STAT3 激活。在第二个目标中，我们将评估S100B/RAGE抑制对肿瘤MP功能的影响。 RAGE/RAGE 配体相互作用将被选择性抑制，并在小鼠神经胶质瘤模型中研究 MG/MP 免疫激活。最后，在最后一个目标中，我们将研究S100B通过肿瘤MG/MP中的RAGE通路激活STAT3的分子机制。这些研究的结果将对当前脑肿瘤的治疗产生重大影响，因为 S100B-RAGE 通路的阻断可能导致 MG/MP 激活并增强针对弥漫性神经胶质瘤的免疫治疗方法。